Summary

Three different drugs—the antidepressant venlafaxine (Effexor® LP) and the hormone therapies medroxyprogesterone acetate (Gestoral®, a progestin) and cyproterone acetate (Androcur®, an antiandrogen)—all reduced the number and intensity of hot flashes in a clinical trial in France of more than 300 men receiving hormonal treatment for advanced prostate cancer. Both hormonal therapies reduced hot flashes to a similar extent and did so about twice as effectively as venlafaxine. However, patients treated with venlafaxine reported better emotional functioning.

Source

Background

Hot flashes, also known as hot flushes, are sudden increases in body temperature (usually lasting five minutes or less) that can cause discomfort, sweating, and flushing of the skin. They occur when fluctuating hormone levels interfere with the body’s ability to regulate its temperature. Most research on hot flashes has been done among women approaching menopause or receiving hormonal cancer treatments, but hot flashes in men are also thought to arise by disrupted thermoregulation caused by fluctuating hormone levels. Thus, it is likely that interventions that relieve hot flash symptoms in women will be effective in men as well.

As many as 80 percent of men receiving androgen suppression therapy for advanced prostate cancer experience hot flashes, which are considered by many patients to be the most difficult side effect of this therapy. Treatments to control hot flashes usually include hormones (both estrogens and nonestrogenic hormones such as progestins). The antiandrogen cyproterone acetate (CPA) has also been used for men experiencing hot flashes, although it is not available in the United States.

A number of nonhormonal therapies, including the selective serotonin reuptake inhibitor (SSRI) antidepressants venlafaxine and paroxetine and the anticonvulsant gabapentin have also shown effectiveness as treatments for hot flashes in women with breast cancer, and there is some evidence that these drugs might relieve hot flashes in men receiving hormonal therapy for advanced prostate cancer. Venlafaxine, however, was found to be less effective than medroxyprogesterone acetate (MPA) in a 2006 trial in women with bothersome hot flashes.

The Study

Between April 2004 and April 2007, researchers enrolled 911 prostate cancer patients from 106 urology centers throughout France. None had received hormone treatments, but all began taking the androgen-suppression drug leuprorelin every three months. After 6 months, 311 patients (34 percent) who had either requested treatment for hot flashes or had reported 14 or more hot flashes in the previous week were randomly assigned to 10 weeks of daily pills: 102 patients to venlafaxine, 101 to CPA, and 108 to MPA.

Before starting to take the study medication, the men kept track for one week of how many hot flashes they had and how severe they were—a hot-flush diary—which provided researchers a baseline measure against which to compare the effects of the study drugs. Patients’ “daily scores” were calculated by multiplying how many hot flashes they had by the average severity of the flashes. Patients were assessed 4, 8, and 12 weeks after beginning treatment, keeping their hot-flush diary for a week in advance of each assessment.

Patients also completed a quality-of-life questionnaire before each visit that asked about their physical, social, emotional, role, and cognitive functioning, as well as fatigue, pain, and nausea and vomiting. The study’s primary outcome was the change in hot flush daily score between baseline and 4 weeks.

The study’s principal investigator was Jacques Irani, M.D., from University Hospital in Poitiers, France. The study was funded by Takeda Laboratories, Puteaux, France. (See the protocol summary.)

Results

After 4 weeks of treatment, the daily hot-flush score improved with all three drugs. The score decreased by 47 percent in patients assigned to venlafaxine, by 84 percent decrease in patients assigned to MPA, and by 95 percent in patients assigned to CPA. Complete relief from hot flush symptoms was reported by 8 percent of the men in the venlafaxine group, 23 percent of those in the MPA group, and 37 percent of those in the CPA group. The difference between venlafaxine and the other two drugs was statistically significant, but the difference between MPA and CPA was not.

Scores on the functional and symptom scales were similar for men in all three groups, with the exception of the emotional functional scale score, which was significantly better with venlafaxine than with either hormone therapy. Only two serious study drug-related adverse events were reported, one in a patient treated with MPA and one in a patient treated with CPA.

Comments

“There is no single standard of care for hot flashes in prostate cancer patients,” said Howard Parnes, M.D., of NCI’s Division of Cancer Prevention. Although each of the three drugs in this study has previously been used with some effectiveness, the study authors believe that this is the first head-to-head-to comparison.

In Europe, CPA “has been used for decades to treat prostate cancer,” the authors write. Consequently, they add, “its use for the treatment of hot flushes could potentially interfere with a planned hormone therapy.” Thus, given MPA’s superior performance to venlafaxine, they “consider that MPA should be considered the standard treatment for hot flushes in men” who are being treated with androgen suppression.

This trial provides more evidence that the research in hot flash treatment is likely to be “sex neutral,” write Charles L. Loprinzi, M.D., and Sherry L. Wolf, M.S., in an accompanying editorial. That is, the results of this study are consistent with those of the 2006 study that found MPA to be more effective than venlafaxine in women with bothersome hot flashes.

Limitations

Not all men who experience hot flashes require or request they be treated. In this study, fewer than 23 percent of patients asked for treatment for their hot flashes. Consequently, the authors do not believe that such treatment should be a standard aspect of androgen-suppression therapy.

CPA is not available in the United States, and an overview of 27 anti-androgen trials published in 2000 found that CPA might actually worsen the disease. Parnes said that “the meta-analysis raised concerns regarding the safety of CPA.”

Finally, longer follow-up is needed to determine whether the treatments will be effective beyond the short time frame evaluated here.

Posted: February
25, 2010

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